Nu, nu-disubstituted beta-haloethylamines



Patented June 2, 1953 N,N-DISUBSTITUTED B-HALOETHYLAMINES Kenneth N. Campbell, South Bend, 'Ind., and Glenn E. Ullyot, Philadelphia, Pa., assignors to Smith, Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application April 13, 1949, Serial No. 87,362

6 Claims.

This invention relates to certain new and useful N,N-disubstituted p-haloethylamines and their inorganic and organic acid addition salts.

The new compounds in accordance with this invention have valuable physiological properties, more particularly sympatholytic or adrenolytic action.

The novel compounds in accordance with this invention are made apparent by the following formula:

l n 2n s N(JJOHX in which R1 designates a heterocyclic radical from the group consisting of quinolyl, furyl, imidazolyl,

X is a member of the group consisting of chlorine and bromine.

More specifically, the compounds included within the above definition will be made apparent by the following formula:

in which R1 designates a heterocyclicradical from the group consisting of 2-quinolyl; Z-quinolyl sub-' stituted with methyl, halogen, methoxy, amino,

dimethylamino; 4-quinolyl; 4=-quinolyl substituted with methyl, halogen, methoxy, amino, dimethylamino, 2-furyl, 2-furyl substituted with methyl halogen; 4-imidazolyl; 4-imidazolyl sub-' stituted with methyl; Z-benzimidazolyl; 5- thiazolyl; thiazolyl; 4-thiazolyl substituted with methyl; amino.

R2 is a member of the group consisting of alkyl containing not more than 8 carbon atoms, i. e.,

5-thiazo1yl substituted with methyl; 4--

2 methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl; aralkyl the alkyl portion of which does not contain more than three carbon atoms; substituted aralkyl groups in which the alkylene portion does not contain more than three carbon atoms and. the substituent of the aryl portion is chosen from the group consisting of methyl, methoxy, amino, dimethylamino, acetylamino and halogen groups.

R3, R4 and R5 are members of the group consisting of hydrogen and alkyl groups selected so that the sum of the carbon atoms in R3, R4 and R5 does not exceed five carbon atoms.

n is an integer not greater than three.

X is a member of the group consisting of chlorine and bromine.

The compounds contemplated by this invention will, as has been indicated, comprise the free base, as made apparent by the above formulae, and inorganic and organic salts thereof, as, for example, hydrochlorides, hydrobromides, sulfates, phosphates, oxalates, maleates, and the like. More specifically, the inorganic and organic salts will be such as are prepared with inorganic and organic acids have an ionization constant not less than 1 10- at 18 C.

In the several formulae set forth hereinafter in connection with description of method for the preparation of compounds in accordance with this invention and by way of example of specific compounds in accordance with this invention, the substituents for R1, R2, R3, R4, R5, n and X appearing in the several formulae hereinafter will be as given in connection with the foregoing general formulae.

The novel N,N-disubstituted s-haloethylamines according to this invention may be pre-- pared by way of example by two general methods.

Method A Procedure according to this method involves as a first step forming a secondary amine having the formula R1CnH2n-NHR as benzylamine, ethylamine, isopropylamine, or-

the like, at hydrogen pressures of 3 to atmospheres and temperature of 20-100 C. in the presence of a hydrogenation catalyst, as, for

example, palladiumplatinum, activated nickel, or the like. A solvent, as, for example, ethyl alcohol, methyl alcohol, glacial acetic acid, or the like, may be employed.

Alternatively, the secondary amines having the above formula may be formed by reaction of a heterocyclic halide having the formula R1CnH2n-X with a primary ainine having the formula RzNI-Ii,

with or without use of a solvent, as alcohol, benzene, or the like, at a temperature of -125 C., the particular temperature depending upon the reactivity of the halide used;

The secondary amines formed by either of the procedures above are reacted with an alkylene oxide, such as ethylene oxide, propylene oxide, or the like, preferably in the presence of asmall amount of water, and in the presence or absence of an inert solvent such as benzene-at tempera tures preferably in the range of -l25 and pressures up to 150 pounds per square inch, with production of an amino alcohol. This reaction andthe amino alcohol product is made apparent It will be apparent that in carrying out the above reactionfor the production of the amino alcohol reagents other than an alkylene oxide may be used. Thus, instead of an alkylene oxide other reagents capable of introducing a ,B hydroxyethyl group, such as ethylene chlorohydrin,

ethylene bromohydrin and propylene briomohydrin, or the like, may be employed. The reaction for forming amino alcohols may be carried out with or without a solvent. Where a solvent is used, such may, for example, be alcohol or benzene.

For the production of the compounds in accordance with this invention, an amino alcohol, for example, formed as above, or its hydrehalide salt, formed in any well knownmanner, is treated with a reagent, for example, thionyl chloride, thionyl bromide, phosphorus trichloride, or the like, which will act to replacethe hydroxyl group with chlorine or bromine. This reaction may be carried out with use of an excess .of the halogenating agent which will also serve as a solvent and, if desired, an inert substance Such as chloroform, benzene, or the like, may beused as a diluent.

By the method as above described the compeunds fwil be produced-in the form of hydroh'alide salts. Free bases thereof may be readily prepared by usual and well known precediire using an inorganic base, such as sbdium carbonate, sodium hydroxide and the like. H

Organic and inorganic salts of the free bases may be readily prepared by a usual and well known procedure using an inorganic or organic acid, as exemplified above, corresponding to the salt desired.

M eth'od B As alternative to the procedure described under Method A for the preparation of the intermediate amino alcohol, this intermediate may be prepared from mohosubstituted ethanolamines by reaction of m'onosubstituted ethanolamines with heteroe cyclic halogen compounds as shown by the following equation:

V solvent. The temperature employed will be Within the range 25-150" 0. and the particular temperature in any given case will depend upon the reactivity 6f the heterocyclic halogen compound used. The final product, the compound in accordancewith-this invention, in the instant case in theform'of a hydrohalide salt, will be formed by reacting the tertiary amino alcohol formed as above with a'reagent capable of replacing the hydroxyl group with chlorine or'bromine, as described above in connection with lVIethod A.

The following specific examples will bemustrative of compounds of the various types 'contemplated by. this inventiomand detailed procedure for their production and will make apparent all the compounds within the scope of this invention and procedure for their production:

EXAMPLE 1 (Method A) .N furfuryl N benzyl e chlorethylamine hydrochloride:

Furfurylbenzylamine is prepared as follows: A solution of 18 .5 g. of'furfurylidene benzyla'mine i (made by reacting benxylamine with furfural) in 75 ml. of alcohol is shaken with hydrogen at 3-4 atmospheresin the presence of 3 g. of freshly-prepared Raney nickel catalyst untilthe theoretical amount of hydrogen-is taken up. The catalyst is removed by filtration and the filtrate distilled. The econdary amine boils at 115-124" 0J4 mm., n 1:5543-1.5580.

A mixture of 20 g. of the above amine, 4.4 g. of ethylene oxide and 2 g. of water is heated. for/16 hours at C. The reaction. mixture is taken up in ether, dried and distilled. There is obtained 10 giof tertiary amino alcohol, B. P. 122 126 G./0.9- mm. The hydrochloride-salt melts at l52154- C. with decomposition.

Seven grams of -N=furfuryl-N-benxylaminoethanol is cooled and treated with '20 ml. of purrfied thionyl chloride and after the initial vigorous reaction has ceased, the mixture is war-med on a water-bathat 45 0. for fifteen minutes. The excess thionyl chloride is removed under reduced pressure and the oily residue is triturated with ether to-make it solidify. The N-furfuryl-N- EDIAMIPLE2 (Method A) N furfuryl N ethyl p chloroethylamine hydrochloride:

H H-CHr-N-dHa-CIIrCLHCl EXAMPLE 3 (Method A) N furfuryl N benzyl 1 amino 2 chloropropane hydrochloride:

The procedure of Example 2 is followed except that, in the second step, propylene oxide is used in place of ethylene oxide.

EXAMPLE 1 (Method B) N- (l-imidazolylmethyl) -N-benzyl-p-chlorethylamine dihydrochloride:

The intermediate N-(4-imidazolylmethyD-N- benzylaminoethanol is prepared by adding 8.0 g. of 4-chloromethylimidazole hydrochloride in small portions to a solution of 25 g. of benzylaminoethanol in 50 ml. of absolute alcohol with cooling in an ice bath. The mixture is allowed to stand at room temperature for thirty minutes and then warmed at 60 C. for three hours. Ether is added, the precipitated solid removed by filtration and the solution evaporated. The residual oil is treated, in n-propanol solution, with dry hydrogen chloride to form the dihydrochloride salt which melts at 182-184 C. with decomposition.

Fifteen milliters of thionyl chloride is added to a solution of 3 g. of the above amino alcohol in 30 ml. of chloroform and the solution is refluxed for twenty minutes. The colorless solid which separates is collected and recrystallized from mixtures of methanol and ether. The 3- chlorethylamine dihydrochloride melts at 194- 194.5 C. with decomposition.

6 EXAMPLE 5 (Method B) N- (4 imidazolylmethyl) -N- (p methoxybenzyl) -fi-chlorethylamine dihydrochloride:

ooH;

This compound is prepared in the same manner as the previous example except that an equivalent quantity of p-methoxybenzylaminoethanol is used instead of benzylaminoethanol. The pmethoxybenzylaminoethanol is prepared in the following manner: One half mole of p-methoxybenzaldehyde and one half mole of ethanol are dissolved in 100 ml. of alcohol and the solution is shaken under a pressure of 3- atmospheres of hydrogen in the presence of 0.5 g. of platinum oxide catalyst. When hydrogen absorption is substantially complete, the solution is filtered and the alcohol is removed by distillation. Distillation of the remainder under reduced pressure yields p -methoxybenzylaminoethanol, B. P. 1'78-185 at 6 mm.

EXAMPLE 6 (Method B) N-lepidyl-N-benzyl 5 chlorethylamine dihydrochloride:

0HzNCHzCHzC1.2HCl

i (5H2 N/ Fifteen grams of lepidine is added to a suspension of 15 g. of N -bromosucoinimide in 50 ml. of carbon tetrachloride at 60 and the mixture is refluxed. for thirty minutes and filtered. hot. On cooling the filtrate, lepidyl bromide, M. P. 88-91", is deposited.

A mixture of 8 g. of lepidyl bromide, 10.8 g. of benzylaminoethanol and 75 ml. of benzene is refiuxed for five hours. After filtering, the solution is evaporated under reduced pressure to give 6 g. of crude N-lepidyl-N-benzylaminoethanol as a light tan oil.

Six grams of the above amino alcohol in 50 ml. of chloroform is cooled while 15 ml. of thionyl chloride is added in small portions. The solu tion is refluxed for a few minutes and the solvent evaporated at room temperature. The residue is dissolved in hot n-propanol solution containing hydrogen chloride. The solution is allowed to cool and insoluble material filtered on. The

product, N lepidyl-N-benzyl-/3-chlorethylamine dihydrochloride, which melts at C.; is obtained by addingether to the filtrate.

EXAMPLE 7 (Method B) N-(6-chlorolepidyl) -N-benzyl 5 chlorethylamine dihydrochloride:

CH Cl if.) Q

aegeeogaes 38 The procedure Blithe-preceding example is fol- (11 lowed. An equivalent. amount of G-chlorolepidine 1 em) d B) .iswusedlas starting material instead of .lepidine.

N-(2 benzimidazolylmethyl) N benzyl 5- EXAMPLE 8 5 chlorethylamineiiihydrochloride:

H (Method B) I N N-lepidyl-N-ethyl-fi-chlorethylamine dihydro- ,1; chloride. r. 10 5 CHr-N-CHzCHaCL2HG1 N l ethanol in 50 ml. of -alcohol. The :rea'etiommixe ture is heated at 50-60 C. for three hours, ether is added and the precipitated benzylaminoethanol a is removed by filtration. :The solvent is evapo- EXAMPLE 9 rated and the tertiary amino alcohol reclrystallized from" aqueous=acet'one,"M. P1 1395- 41. C.

(Method B) The dihydrochloridamelts'at 178 -179.5*C. 1-'N-;quinaldyl-N ethyl-Bechlorethylamine idihyirty-two r ms of he b ve am l h l h id dihydrochloricle is added to '71 g. of thionyl chloride and the mixture refluxed for two hours. Re-

moval of the excess thion'ylchloride in vacuo leaves the B-chlorethylamine dihydrochloride This compound isprepared by the method described under Example 8. 'In" the second step, .eth'ylaminoethanol is substituted for 'benzyl- ".aminoethanol.

A CH2 NTG H2CHCL2HC1 which, after recrystallization fI'Om 8.1001101 and.

' 2H ether, melts at 164-166 C. 5

EXAMPLElZ The procedurerof. Example 8 is followed Method,A Bromoquinaldine (see Hammich: J. Chem. Soc."" 1926, 1302) is reactedwith ethylaminoethanol in B w ebenzylwfi bromobenzene solution. The resulting amino alcohol is fl hydroblomidei then treated with thionyl chloride as :in the above CH3: 0 CH2TC-H2+N1CHr=CH2TC12QaH204 Hi This compound is prepared in the manner described in Example 2. In the first step an equivalent amount of furylacetone is used instead of furfural. In the final step, thionyl bromide is employed in place of thionyl chloride.

.Flhet compoundsof. this invention may :be 'iso- A solution of ;155 latedvas freelcases by addition'of =an -aqueous e'thyl) :thiazble (See "Buchmanm J Am c 1 solutionoffla *ba-se to a salt'asiillustratecliin Exiisocitaiaos (1936)) 10 ml..of benzene...is -amp1e "Additionofen acid, vill-anysm'tallle treated w of benzymminoethanol and the solvent; to the free baseforms-an-acid addition "mixture heated at for. 17 hours. On cooling, Salt This. procedure a ed: a ain in Ex- 0 benzylaminoethanol .hydrobromide. is deposited 60 m ian'd is removed by filtration. uDistillatiomof. the iIEXAMPLE 13 filtratefgives8 g. of intermediate amino alcohol, 1

13: P: 174-175 0.. 10.05 mm. (Medwd B) Twenty milliliters of thionyl chloride is added 5-N-(2eamino-4-thia 0 y y J N --ethyl 5- to a cooled solution of8 g. of the above amino 5 f:bhlorethylamine'lhydrochlorideI alcohol in 50 ml. of'chloroform and the solution is CHPNGHQGECLHC} refluxed -for fifteen'minutes. *Evaporation'of-the I i v 02H solvent leaves an oily residuawhich 'is treated with sodium .bicarbonatesolution. The waterinsoluble product is extracted with ether. The ZO 'N z oxalate salt is formed byzaddi-nga solution of 6 g. This compound will be prepared 'in'- the same of anhydrous oxalic acid-inEEO m1. of alcohol to .'ma,nner1a EXamp1e 1.0 startingmaterials the dried ether solution of 'theiree' base. The will be 2=amino=4 '(chloromethy1)thiozole-and dioxalate salt so formed is hydrated with one ethy1aminoethano1 -instead -'of '4'-methyl 5-(;8- molecule of water and melts at bromoethyl)thiozole andhbenzylaminoethanol.

EXAMPLE 14 (Method 12;)

1 EXAMPLE 17 (M ethod A) N furfuryl N (p-dimethylaminobenzyl) -B- methoxylepidyl) (p methoxyben chlorethylamine dlhYdIOChIOIldC-JZ zyl) -fl-chlorethylamine dihydrochloride:

CH2 CIR-30w N EXAMPLE (Method B) N- (l-imidazolylethyl) -N-benzyl-fl-chlorethylamine dihydrochloride:

This compound will be prepared in the same manner as Example 4 except that l-(fi-chloroethyl) imiazole hydrochloride will be used in place of 4-chloromethylimidazole hydrochloride. The 4-(B-chloroethy1) imiazole hydrochloride will be added to an alcoholic solution of benzylamine and then refluxed for six to eight hours. The product will be worked up and reacted with thionyl chloride as described under Example 4.

EXAlVEPLE 16 (Method B N (2 benzimidazolylm-ethyl) N-(p-methylbenzyl) -,8-chlorethylamine dihydrochloride:

l CH3 p-Methylbenzylaminoethanol will be prepared from p-methylbenzaldehyde and ethanolamine by the method described in Example 5 for the p-methoxy compound. p-Methylbenzylaminoethanol boils at M l-148 at 4 mm. and forms a hydrochloride melting at 113-115 The -p-methylbenzylaminoethanol will be re-- acted with 2-ch1oromethylbenzimidozole in the same manner as described for Example 11. The product will be refluxed with thionyl chloride to form the desired fi-chlorethylamine.

This compound will be prepared in the same manner as Example 1. In the first step, p-dimethylaminobenzylamine will be employed instead of benzylamine.

EXAMPLE 18 (Method B) N (4 imidazolylmethyl) -N- (p-acety1aminobenzyl) -B-chlorethylamine dihydrochloride:

p-Acetylaminobenzylaminoethanol will be prepared by hydrogenation of a solution of p-acetylaminobenzaldehyde and ethanolamine in the same manner as described for the preparation of p-methoxybenzylaminoethanol in Example 14.

The procedure of Example 4 Will be followed in the reaction of 4-chloromethylamidazole hydrochloride with p-acetylaminobenzylaminoethanol to form N (-imidazolylmethyl) -l T-(p-acety1- aminobenzyl) aminoethanol. The dihydrochl-oride of this amino alcohol will be treated with thionyl chloride in chloroform solution to for the end product.

EXAMPLE 19 (M ethod B) N (4-imidazolylmethyl) -N-(p-aminobenzy1) fl-chlorethylamine trihydrochloride OH2N'OH2CH2C1.3HC1 l I NH 0H2 N (4 imidazolylmethyl)-N-(p-acety1aminobenzyDaminoethanol, prepared as described in the previous example, will be heated in aqueous alcohol solution of sodium hydroxide to remove the acetyl group. The resulting N -(4-imidazolylmethyD-N-(p-amino benzyl) aminoethanol will be converted to the trihydrochloride salt with anhydrous hydrogen chloride and this salt will'be treated with thionyl chloride in chloroform solution as described in Example 4.,

The procedure of Example 4 will be followed. In the first step n-amylaminoethanol will be used in place of benzylaminoethanol.

EXAMPLE 21 (Method B) N (Z-benzimidazolylmethyl) -N-(4-heptyl) -2- amino-l-chloropropane dihydrochloride:

H cm CCHz-.NCHCHzCl.2HCl

I cinema-03H? In the procedure of Example 11, 2-chloromethylbenzimidazole will be reacted with Z-( l-heptylamino) propanol insteadoi benzylaminoethanol. The product, as the dihydrochloride salt, will be reacted with thionylchloride to form the above compound.

EXAMPLE 22 (Method B) N (4 methyl-fi-thiazolylethyl) -N-isoprpyl- 2-amlno-3-chloropentane hydrochloride:

The procedure of Example 10. will be followed. In the, first step an equivalent amount of'N-isopropyl-2-amino-3-pentanol. will be employed instead of benzylaminoethanol. The N-isopropyl- 2-amino-3pentanol will be formed by adding. acetone to an alcoholic solution of 2-amino-3- pentanol and agitating the resulting solution under hydrogen pressure in the presence of platinum catalyst,

It will be self-evident to those skilled 1n the art that in the foregoing examples illustrative of the production of chloride .hydrochlorides by the procedures clescribedbromide hydrobromides will be produced with the use, for example, of thionyl bromide in place of thionyl chloride in the final step. Thus, the foregoing specific examples of chloride hydrochlorides serve as specific examples of bromide hydrobromides by simply replacing CLHCl in the several formulae with Br.HBr.

It will be noted, as is perfectly apparent, that thechloride hydrochlorides and bromide hydrobromides of the foregoing examples may beisolated as free bases by the treatment of the salts with a. solution of a base as, for example, sodium bicarbonate, sodium hydroxide, or the like, in well known manner. Hence, the foregoing specific examples of chloride .hydrochlorides and bromide hydrobromideswill serve to specifically exemplify the corresponding free bases by the 12 mere elimination iromithe several formulae of HCl or HBr.

Again, the inorganic and organic salts of the free bases exemplified above will be formed in wellsknown manner: by treatment of the, free bases with. an inorganic or organic, acid corresponding to the salts desired and the several foregoing. specific exemples Will be specifically illustrative of inorganic-and. organic salts by the simple expedient of substituting in the formulae given the desired inorganic or organic acid radical for HCl or HBr.

What we claim and desire'to protect by Letters Patent is:

l. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula:

in which R1 is a heterocyclic radical selected from the group consisting of unsubstituted quinolyl, furyl, imidazolyl;benzimidazolyl, thiazolyl, and methyl substituted quinolyl, furyl, imidazolyl, benzimidazolyl, and thiazolyl; R2 is selected from the group consisting of benzyl, methyl benzyl, methoxy benzyl, and halo benzyl radicals; R3 is selected 'from the group consisting of hydrogen and methyl radicals; his an integer not greater than three and not less than one; andX is selected from the group consisting of chlorine and bromine.

The compound N -furfuryl N benzyl B- chlorethylamine hydrochloride having the struc- 3. The compound N-(4-imidazolylmethyD-N- benzyl-fi-chlorethylamine' dihydrochloride having the structure:

4. The compound N-lepidyl-N-benzyl-e-chlorethylamine dihydrochloride having the structure:

5'. "The compound N i-methyl-5-thiazoly1eth- Y1) fi ethylamine dioxalate having the structure: n

13 14 6. The compound N-(2-benzimidazo1y1meth- OTHER REFERENCES yl) -N-benzy1-p-ch1orethy1amine dihydrochloride having the structure; Goldm et aL: J. Pharm. Exp. Therap., v01. 94,

H p. 256 (1948). N Fruton et a1.: J. Org. Chem, v01. 11, pp. 5'71- C-CHzNCHaCHa-Cl 21101 5 585 (1946') N Huttrer: Enzymologia, vol. 12, pp. 304, 305,

319, 320, and 321 (April 1948).

Fieser and Fieser: Organic Chemistry, (D. C. Heath and 00., Boston, 1944), p. 32. 10 Nickel-son et aL: Federation Proceedings, Vol.

Beyer: Physiological Rev., Apr. 1946, p. 191. KENNETH CAMPBELL- Williams: Detoxification Mechanisms (John GLENN ULLYOT- 15 Wiley, New York, 1947), pp. 194-197.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 1,949,247 Eisleb Feb. 27, 1934 20 

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ACID ADDITION SALTS, SAID FREE BASE HAVING THE FORMULA: 